LY3214996 and Cetuximab Alone or in Combination With Abemaciclib for the Treatment of Unresectable or Metastatic Colorectal Cancer

This phase Ib/II trial investigates the side effects and best dose of LY3214996 when given together with cetuximab alone or in combination with abemaciclib and to see how well they work in treating patients with colorectal cancer that cannot be removed by surgery (unresectable) and/or has spread to other places in the body (metastatic). Cetuximab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. LY3214996 and abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving LY3214996 and cetuximab alone or in combination with abemaciclib may help treat patients with colorectal cancer.

Inclusion Criteria: * Provision of signed Informed Consent prior to any screening procedures being performed. The informed consent process will be conducted in accordance with MD Anderson Office of Clinical Research SOP 04 and as indicated in Appendix 2. * Age ≥18 years at the time of informed consent. * Histologically (or cytologically) confirmed diagnosis of adenocarcinoma of the colon or rectum, with clinical confirmation of unresectable and/or metastatic disease that is measureable according to RECIST1.1 criteria. * Baseline tissue-based KRAS, NRAS, EGFR, BRAF wild-type tumor. If MEK1 was tested, must be wild-type tumor * Prior treatment with at least one systemic chemotherapy regimen for mCRC, or recurrence/progression with development of unresectable or metastatic disease within 6 months of adjuvant chemotherapy for resected colorectal cancer. * Participants who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events \[CTCAE\] Grade .1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to randomization. A washout period of at least 21 days is required between last chemotherapy dose and randomization (provided the participant did not receive radiotherapy). * Participants who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and randomization * Left-sided primary tumor * Prior treatment with, and progression on, anti-EGFR therapy (cetuximab or panitumumab). * ECOG performance status ≤ 1. * Adequate bone marrow, organ function and laboratory parameters: * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, * Hemoglobin (Hgb) ≥ 9 g/dL with or without transfusions, * Platelets (PLT) ≤ 100 x 109/L without transfusions, * AST and/or ALT ≤ 2.5 x upper limit of normal (ULN) * Total bilirubin ≤ 1.5 x ULN and \< 2 mg/dL Note: Participants who have a total bilirubin level \> 1.5 x ULN will be allowed if their indirect bilirubin level is ≤ 1.5 x ULN * Serum Creatinine ≤ 1.5 x ULN, or calculated creatinine clearance (determined as per Cockcroft-Gault) ≥ 50mL/min at screening. * QTc interval ≤ 480 ms (preferably the mean from triplicate ECGs); * Able to take oral medications. * Female participants are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from screening through follow-up if of childbearing potential. Note: Permitted contraception methods include: male condom with spermicide, female condom with spermicide, diaphragm with spermicide, cervical sponge, or cervical cap with spermicide. Also see the definition of highly effective method of contraception in Appendix 1. These should be communicated to the participants and their understanding confirmed. For all females, the pregnancy test result must be negative within 24 hours of starting treatment on study and within 24 hours prior to each cycle. Males must agree to take appropriate precautions to avoid fathering a child from screening through 100 days following the end of therapy. Exclusion Criteria: * History of a Grade 3 or 4 allergic reaction or intolerability attributed to cetuximab. * Right-sided or transverse colonic primary tumor. * Baseline tissue-based KRAS, NRAS, EGFR, BRAF and MEK1 mutated tumor * Active infection requiring concurrent antibiotic use. * Currently using concomitant medications that are strong inhibitors or inducers of CYP3A4. * Previously completed or withdrawn from this study or any other study investigating an ERK1/2 inhibitor. * Any known symptomatic brain metastasis. Note: Participants previously treated or untreated for this condition who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Known brain metastases must be stable for ≥ 4 weeks, with imaging (e.g., magnetic resonance imaging \[MRI\] or computed tomography \[CT\]) demonstrating no current evidence of progressive brain metastases at screening. * Known leptomeningeal disease * Previous or concurrent malignancy within 3 years of study entry, with the following exceptions: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy; other solid tumors treated curatively without evidence of recurrence for at least 3 years prior to study entry. * Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: * History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) \